abstract: Electrical nerve stimulation is a promising drug-free technology that could treat a variety of ailments and disorders. Methods like Vagus Nerve Stimulation have been used for decades to treat disorders like epilepsy, and research with non-invasive vagus nerve stimulation has shown similar effects as its invasive counterpart. Non-invasive nerve stimulation methods like vagus nerve stimulation could help millions of people treat and manage various disorders. This study observed the effects of three different non-invasive nerve stimulation paradigms in human participants. The first study analyzed the safety and efficacy of transcutaneous auricular vagal nerve stimulation in healthy humans using a bilateral stimulation protocol with uniquely designed dry-hydrogel electrodes. Results demonstrate bilateral auricular vagal nerve stimulation has significant effects on specific parameters of autonomic activity and is safe and well tolerated. The second study analyzed the effects of non-invasive electrical stimulation of a region on the side of the neck that contains the Great Auricular Nerve and the Auricular Branch of the Vagus Nerve called the tympanomastoid fissure on golf hitting performance in healthy golfers. Results did not show significant effects on hitting performance or physiological activity, but the nerve stimulation had significant effects on reducing state-anxiety and improving the quality of feel of each shot. The third study analyzed the effects of non-invasive nerve stimulation of cervical nerves on the back of the neck on putting performance of yips-affected golfers. Results demonstrated that cervical nerve stimulation had significant effects on improving putting performance but did not have significant effects on physiological activity. Data from these studies show there are potential applications for non-invasive electrical nerve stimulation for healthy and athletic populations. Future research should also examine the effects of these stimulation methods in clinical populations. / Dissertation/Thesis / Doctoral Dissertation Biomedical Engineering 2020

Objective: Percutaneous tibial nerve stimulation (PTNS) is used to treat refractory urinary frequency, urgency, and urgency urinary incontinence. To date, it is not approved by the US Food and Drug Administration in the treatment of chronic pain syndromes, and its use in the treatment of chronic clitoral pain has not been reported. Methods: We describe 2 cases of women who presented with symptoms of urgency urinary incontinence, urinary frequency, and clitoral pain. After inadequate response to conservative treatment of their urinary symptoms, they received PTNS. Results: By the 12th session, significant improvement in urinary symptoms and resolution of clitoral pain were noted. Conclusions: The findings of this report suggest that PTNS may be a therapeutic option in patients with idiopathic clitoral pain.

In this study, we experimentally elevated levels of octopamine and serotonin in an orb-weaving spider, and observed the effects on the antipredator behavior thanatosis (death feigning), activity level, and running speed. We found that octopamine significantly shortened the duration of thanatosis, and its effect wore off over 24 h. We also found that serotonin significantly lengthened thanatosis, but in this case, the effect persisted for over 24 h. Neither octopamine nor serotonin affected the general activity or running speed of the spiders. To our knowledge, this is the first study to directly explore the role of biogenic amines on a specific antipredator behavior in spiders. Given that spiders must be both aggressive toward prey, yet wary of predators, we believe that this system will be an outstanding model to explore connections between behavioral ecology and neurochemistry.

During myocardial ischemia, the cranial cervical spinal cord (C1-C2) modulates the central processing of the cardiac nociceptive signal. This study was done to determine 1) whether C2 SCS-induced release of an analgesic neuropeptide in the dorsal horn of the thoracic (T4) spinal cord; 2) if one of the sources of this analgesic peptide was cervical propriospinal neurons, and 3) if chemical inactivation of C2 neurons altered local T4 substance P (SP) release during concurrent C2 SCS and cardiac ischemia. Ischemia was induced by intermittent occlusion of the left anterior descending coronary artery (CoAO) in urethane-anesthetized Sprague-Dawley rats. Release of dynorphin A (1-13), (DYN) and SP was determined using antibody-coated microprobes inserted into T4. SCS alone induced DYN release from laminae I-V in T4, and this release was maintained during CoAO. C2 injection of the excitotoxin, ibotenic acid, prior to SCS, inhibited T4 DYN release during SCS and ischemia; it also reversed the inhibition of SP release from T4 dorsal laminae during C2 SCS and CoAO. Injection of the κ-opioid antagonist, nor-binaltorphimine, into T4 also allowed an increased SP release during SCS and CoAO. CoAO increased the number of Fos-positive neurons in T4 dorsal horns but not in the intermediolateral columns (IML), while SCS (either alone or during CoAO) minimized this dorsal horn response to CoAO alone, while inducing T4 IML neuronal recruitment. These results suggest that activation of cervical propriospinal pathways induces DYN release in the thoracic spinal cord, thereby modulating nociceptive signals from the ischemic heart.

Our objective was to determine whether neuronally induced atrial arrhythmias can be modified by α-adrenergic receptor blockade. In 30 anesthetized dogs, trains of five electrical stimuli (1 mA; 1 ms) were delivered immediately after the P wave of the ECG to mediastinal nerves associated with the superior vena cava. Regional atrial electrical events were monitored with 191 atrial unipolar electrodes. Mediastinal nerve sites were identified that reproducibly initiated atrial arrhythmias. These sites were then restimulated following 1 h (time control, n = 6), or the intravenous administration of naftopidil (α1-adrenergic blocker: 0.2 mg/kg, n = 6), yohimbine (α2-adrenergic blocker: 1 mg/kg, n = 6) or both (n = 8). A ganglionic blocker (hexamethonium: 1 mg/kg) was tested in four dogs. Stimulation of mediastinal nerves sites consistently elicited atrial tachyarrhythmias. Repeat stimulation after 1 h in the time-control group exerted a 19% decrease of the sites still able to induce atrial tachyarrhythmias. Hexamethonium inactivated 78% of the previously active sites. Combined α-adrenoceptor blockade inactivated 72% of the previously active sites. Bradycardia responses induced by mediastinal nerve stimulation were blunted by hexamethonium, but not by α1,2-adrenergic blockade. Naftopidil or yohimbine alone eliminated atrial arrhythmia induction from 31% and 34% of the sites (similar to time control). We conclude that heterogeneous activation of the intrinsic cardiac nervous system results in atrial arrhythmias that involve intrinsic cardiac neuronal α-adrenoceptors. In contrast to the global suppression exerted by hexamethonium, we conclude that α-adrenoceptor blockade targets intrinsic cardiac local circuit neurons involved in arrhythmia formation and not the flow-through efferent projections of the cardiac nervous system.

Our objective was to determine whether electrical neuromodulation using spinal cord stimulation (SCS) mitigates transient ischemia-induced ventricular infarction and, if so, whether adrenergic neurons are involved in such cardioprotection. The hearts of anesthetized rabbits, subjected to 30 min of left anterior descending coronary arterial occlusion (CAO) followed by 3 h of reperfusion (control), were compared with those with preemptive SCS (starting 15 min before and continuing throughout the 30-min CAO) or reactive SCS (started at 1 or 28 min of CAO). For SCS, the dorsal C8-T2 segments of the spinal cord were stimulated electrically (50 Hz, 0.2 ms, 90% of motor threshold). For preemptive SCS, separate groups of animals were pretreated 15 min before SCS onset with 1) vehicle, 2) prazosin (α1-adrenoceptor blockade), or 3) timolol (β-adrenoceptor blockade). Infarct size (IS), measured with tetrazolium, was expressed as a percentage of risk zone. In controls exposed to 30 min of CAO, IS was 36.4 ± 9.5% (SD). Preemptive SCS reduced IS to 21.8 ± 6.8% (P < 0.001). Preemptive SCS-mediated infarct reduction was eliminated by prazosin (36.6 ± 8.8%) and blunted by timolol (29.4 ± 7.5%). Reactive SCS did not reduce IS. SCS increased phosphorylation of cardiac PKC. SCS did not alter blood pressure or heart rate. We conclude that preemptive SCS reduces the size of infarcts induced by transient CAO; such cardioprotection involves cardiac adrenergic neurons.

Effects of substance P (SP) and selective tachykinin agonists on neurotransmission at guinea-pig intracardiac ganglia were studied in vitro. Voltage responses of neurons to superfused tachykinins and nerve stimulation were measured using intracellular microelectrodes. Predominant effects of SP (1 μM) were to cause slow depolarization and enable synaptic transmission at low intensities of nerve stimulation. Augmented response to nerve stimulation occurred with 29 of 40 intracardiac neurons (approx. 73%). SP inhibited synaptic transmission at 23% of intracardiac neurons but also caused slow depolarization. Activation of NK3 receptors with 100 nM [MePhe 7]neurokinin B caused slow depolarization, enhanced the response of many intracardiac neurons to low intensity nerve stimulation or local application of acetylcholine, and triggered action potentials independent of other stimuli in 6 of 42 neurons. The NK1 agonist [Sar 9,Met(O2)11]SP had similar actions but was less effective and did not trigger action potentials independently. Neither selective agonist inhibited cholinergic neurotransmission. We conclude that SP can function as a positive or negative neuromodulator at intracardiac ganglion cells, which could be either efferent neurons or interneurons. Potentiation occurs primarily through NK3 receptors and may enable neuronal responses with less preganglionic nerve activity. Inhibition of neurotransmission by SP is most likely explained by the known blocking action of this peptide at ganglionic nicotine receptors.

abstract: Previously accomplished research examined sensory integration between upper limb proprioception and tactile sensation. The active proprioceptive-tactile relationship points towards an opportunity to examine neuromodulation effects on sensory integration with respect to proprioceptive error magnitude and direction. Efforts to improve focus and attention during upper limb proprioceptive tasks results in a decrease of proprioceptive error magnitudes and greater endpoint accuracy. Increased focus and attention can also be correlated to neurophysiological activity in the Locus Coeruleus (LC) during a variety of mental tasks. Through non-invasive trigeminal nerve stimulation, it may be possible to affect the activity of the LC and induce improvements in arousal and attention that would assist in proprioceptive estimation. The trigeminal nerve projects to the LC through the mesencephalic nucleus of the trigeminal complex, providing a pathway similar to the effects seen from vagus nerve stimulation. In this experiment, the effect of trigeminal nerve stimulation (TNS) on proprioceptive ability is evaluated by the proprioceptive estimation error magnitude and direction, while LC activation via autonomic pathways is indirectly measured using pupil diameter, pupil recovery time, and pupil velocity. TNS decreases proprioceptive error magnitude in 59% of subjects, while having no measurable impact on proprioceptive strategy. Autonomic nervous system changes were observed in 88% of subjects, with mostly parasympathetic activation and a mixed sympathetic effect. / Dissertation/Thesis / Masters Thesis Biomedical Engineering 2019

Military training and operations can place significant demands on cognitive and physical resources of service members, resulting in heightened stress and fatigue, elevated risk of accidents and injuries, and diminished cognitive and occupational performance. Transcutaneous electrical stimulation (TES) is a novel, non-invasive neuromodulatory technique being investigated as a means to improve alertness and preserve performance under stress with few-to-no side effects. Despite the recent increase in research using TES, few studies have explored the effects of stimulation of the trigeminal nerve on cognition and the human stress response. Therefore, the aims of this study were to elucidate the effects of TES on biochemical and physiological responses to stress, cognition, and marksmanship performance under cognitive load. Participants in this repeated measures, crossover-design study included 23 healthy male (n = 18) and female (n = 5) civilians and members of the military ranging in age from 19 to 37 (mean 24.00 ± 5.65) years. Study procedures occurred in the afternoon on five consecutive days, including two testing days involving administration of active or sham TES to the right supraorbital region of the face using a commercially-available device (Thync One, Cerevast Therapeutics). To evaluate the effects of TES on the stress response, participants were required to complete a prolonged, cognitively challenging target discrimination task using a simulated firing range, which has been previously demonstrated to induce a reliable stress response in human research volunteers. Computer-assisted cognitive tasks were administered before and after rifle marksmanship in order to provide complementary assessment of functional domains challenged during the marksmanship task. Salivary markers of cortisol and α-amylase were collected at several time points during the testing day, and electrocardiography (ECG) and photoplethysmography (PPG), both markers of heart rate variability and stress responding, were monitored continuously. Linear mixed models with random slopes were used to analyze the effect of stimulation condition (active versus sham TES) on marksmanship and cognitive, physiological, and salivary outcomes across the testing period and at each measurement time point. No significant effects of stimulation condition or the interactions between stimulation condition and measurement time point were found for salivary stress biomarkers (punadj range 0.12 – 0.98) or for cognitive (punadj range 0.25 – 0.88) and physical workload (punadj range 0.31 – 0.79). There were no significant effects of stimulation condition on time-series indicators of heart rate variability (punadj range 0.10 – 0.96) except for pNN50 when measured with PPG (β = -4.97, punadj = 0.04, padj = n.s., d < 0.01). There were, however, significant stimulation condition by time interaction effects on mean heart rate, mean R-R interval, SDNN, RMSSD, and pNN50 (punadj range 0.12 – 0.98, d range < 0.01 – 0.02), indicating that trigeminal TES using the Thync One device increased activity of both the sympathetic and parasympathetic nervous systems during marksmanship and cognitive testing. Similar effects were noted on frequency-series indicators of heart rate variability using both ECG and PPG, in which stimulation condition effects were noted on ECG high frequency absolute (β = 8.50, punadj < 0.01, padj = 0.01, d < 0.01) and relative powers (β = -8.54, punadj < 0.01, padj = 0.01, d < 0.01), as well as PPG very low frequency power (β = -367.98, punadj < 0.01, padj = n.s., d = 0.12). Effects of the interaction between stimulation condition and measurement time point were noted on very low, low, and high frequency powers (punadj range < 0.01 – 0.048, d range < 0.01 – 0.21), as well as the ratio of low- to high-frequency powers in ECG (punadj range < 0.01 – 0.048, d < 0.01 for all). These results also suggest that trigeminal TES increased activity of both the sympathetic and parasympathetic nervous systems during marksmanship and cognitive testing. Furthermore, significant effects of stimulation condition were noted on marksmanship shot accuracy (β = 0.14, punadj = 0.01, padj = n.s., d = 0.60) and distance of shots from the targets’ center of mass (β = -0.08, punadj = 0.02, padj = n.s., d = 0.56), indicating that trigeminal TES impaired shot accuracy. There were also significant condition-by-time interaction effects on target detection latency (β = 220.46, punadj = 0.04, padj = n.s., d = 0.49); significant impairments in shot latency observed during the first marksmanship session in the active TES condition only resolved by the second marksmanship session. There were no significant effects of TES on accuracy or response times for neuropsychological tasks assessing response inhibition, sustained attention, and working memory (punadj range 0.09 – 0.98). Active trigeminal TES did, however, significantly reduce the standard deviation of response times on a measure of sustained attention and response inhibition (β = -16.29, punadj = 0.045, padj = n.s., d = 0.43). Although the literature suggests that TES may benefit stress and performance, these results do not support that conclusion. Overall, these analyses found that TES using a commercially available device did not influence chemical biomarkers of stress, but did influence markers of physiological stress, as well as cognitive and marksmanship performance under high cognitive load. TES was associated with impairments in marksmanship performance as well as increases in both sympathetic and parasympathetic nervous system activity. Further studies using different stimulation parameters, including multiple sessions of stimulation, will be necessary to more fully characterize possible influences of trigeminal nerve stimulation on stress responding and marksmanship performance or other military relevant tasks. In addition, this project underscores the need for more investigation into the mechanisms of effect of the Thync One device and other devices applying TES of the trigeminal nerve.

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